Rapamune

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Rapamune

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Increased Susceptibility To Infection And The Possible
Development Of Lymphoma

Increased susceptibility to infection and the possible
development of lymphoma and other malignancies, particularly of the skin, may
result from immunosuppression. The rates of lymphoma/lymphoproliferative
disease observed in Studies 1 and 2 were 0.7-3.2% (for Rapamune-treated
patients) versus 0.6-0.8% (azathioprine and placebo control) [see ADVERSE
REACTIONS]. Oversuppression of the immune system can also increase
susceptibility to infection, including opportunistic infections such as
tuberculosis, fatal infections, and sepsis. Only physicians experienced in
immunosuppressive therapy and management of organ transplant patients should
use Rapamune. Patients receiving the drug should be managed in facilities
equipped and staffed with adequate laboratory and supportive medical resources.
The physician responsible for maintenance therapy should have complete
information requisite for the follow-up of the patient.

The safety and efficacy of Rapamune as immunosuppressive
therapy have not been established in liver transplant patients; therefore, such
use is not recommended. The use of Rapamune has been associated with adverse
outcomes in patients following liver transplantation, including excess
mortality, graft loss and Hepatic ArteryThrombosis (HAT).

In a study in de novo liver transplant patients, the use
of Rapamune in combination with tacrolimus was associated with excess mortality
and graft loss (22% in combination versus 9% on tacrolimus alone). Many of
these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant
patients, the use of Rapamune in combination with cyclosporine or tacrolimus
was associated with an increase in HAT (7% in combination versus 2% in the
control arm); most cases of HAT occurred within 30 days post-transplantation,
and most led to graft loss or death.

In a clinical study in stable liver transplant patients
6-144 months post-liver transplantation and receiving a CNI-based regimen, an
increased number of deaths was observed in the group converted to a
Rapamune-based regimen compared to the group who was continued on a CNI-based
regimen, although the difference was not statistically significant (3.8% versus
1.4%) [see Clinical Studies].

Lung Transplantation – Bronchial Anastomotic Dehiscence

Cases of bronchial anastomotic dehiscence, most fatal,
have been reported in de novo lung transplant patients when Rapamune has been
used as part of an immunosuppressive regimen.

The safety and efficacy of Rapamune as immunosuppressive
therapy have not been established in lung transplant patients; therefore, such
use is not recommended.

Angioedema

Rapamune has been associated with the development of
angioedema. The concomitant use of Rapamune with other drugs known to cause
angioedema, such as ACE-inhibitors, may increase the risk of developing
angioedema.

Fluid Accumulation And Wound Healing

There have been reports of impaired or delayed wound
healing in patients receiving Rapamune, including lymphocele and wound
dehiscence [see ADVERSE REACTIONS]. mTOR inhibitors such as sirolimus
have been shown in vitro to inhibit production of certain growth factors that
may affect angiogenesis, fibroblast proliferation, and vascular permeability.
Lymphocele, a known surgical complication of renal transplantation, occurred
significantly more often in a dose-related fashion in patients treated with
Rapamune [see ADVERSE REACTIONS]. Appropriate measures should be
considered to minimize such complications. Patients with a body mass index
(BMI) greater than 30 kg/m² may be at increased risk of abnormal
wound healing based on data from the medical literature.

There have also been reports of fluid accumulation,
including peripheral edema, lymphedema, pleural effusion, ascites, and
pericardial effusions (including hemodynamically significant effusions and
tamponade requiring intervention in children and adults), in patients receiving
Rapamune.

Hyperlipidemia

Increased serum cholesterol and triglycerides requiring
treatment occurred more frequently in patients treated with Rapamune compared
with azathioprine or placebo controls in Studies 1 and 2 [see ADVERSE
REACTIONS]. There were increased incidences of hypercholesterolemia
(43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving Rapamune
compared with placebo controls (each 23%). The risk/benefit should be carefully
considered in patients with established hyperlipidemia before initiating an
immunosuppressive regimen including Rapamune.

Any patient who is administered Rapamune should be
monitored for hyperlipidemia. If detected, interventions such as diet,
exercise, and lipid-lowering agents should be initiated as outlined by the
National Cholesterol Education Program guidelines.

In clinical trials of patients receiving Rapamune plus
cyclosporine or Rapamune after cyclosporine withdrawal, up to 90% of patients
required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid
therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of
patients had fasting serum cholesterol levels > 240 mg/dL and triglycerides
above recommended target levels. The concomitant administration of Rapamune and
HMG-CoA reductase inhibitors resulted in adverse events such as CPK elevations
(3%), myalgia (6.7%) and rhabdomyolysis ( < 1%). In these trials, the number
of patients was too small and duration of follow-up too short to evaluate the
long-term impact of Rapamune on cardiovascular mortality.

During Rapamune therapy with or without cyclosporine,
patients should be monitored for elevated lipids, and patients administered an
HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible
development of rhabdomyolysis and other adverse effects, as described in the
respective labeling for these agents.

Renal Function

Renal function should be closely monitored during the
co-administration of Rapamune with cyclosporine, because long-term
administration of the combination has been associated with deterioration of
renal function. Patients treated with cyclosporine and Rapamune were noted to
have higher serum creatinine levels and lower glomerular filtration rates
compared with patients treated with cyclosporine and placebo or azathioprine
controls (Studies 1 and 2). The rate of decline in renal function in these
studies was greater in patients receiving Rapamune and cyclosporine compared
with control therapies.

Appropriate adjustment of the immunosuppressive regimen,
including discontinuation of Rapamune and/or cyclosporine, should be considered
in patients with elevated or increasing serum creatinine levels. In patients at
low-to moderate-immunologic risk, continuation of combination therapy with
cyclosporine beyond 4 months following transplantation should only be
considered when the benefits outweigh the risks of this combination for the
individual patients. Caution should be exercised when using agents (e.g.,
aminoglycosides and amphotericin B) that are known to have a deleterious effect
on renal function.

In patients with delayed graft function, Rapamune may
delay recovery of renal function.

Proteinuria

Periodic quantitative monitoring of urinary protein
excretion is recommended. In a study evaluating conversion from calcineurin
inhibitors (CNI) to Rapamune in maintenance renal transplant patients 6-120
months post-transplant, increased urinary protein excretion was commonly
observed from 6 through 24 months after conversion to Rapamune compared with
CNI continuation [see Clinical Studies, ADVERSE REACTIONS].
Patients with the greatest amount of urinary protein excretion prior to
Rapamune conversion were those whose protein excretion increased the most after
conversion. New onset nephrosis (nephrotic syndrome) was also reported as a
treatment-emergent adverse event in 2.2% of the Rapamune conversion group
patients in comparison to 0.4% in the CNI continuation group of patients.
Nephrotic range proteinuria (defined as urinary protein to creatinine ratio
> 3.5) was also reported in 9.2% in the Rapamune conversion group of
patients in comparison to 3.7% in the CNI continuation group of patients. In
some patients, reduction in the degree of urinary protein excretion was
observed for individual patients following discontinuation of Rapamune. The
safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance
renal transplant patients have not been established.

Latent Viral Infections

Immunosuppressed patients are at increased risk for
opportunistic infections, including activation of latent viral infections.
These include BK virus-associated nephropathy, which has been observed in
patients receiving immunosuppressants, including Rapamune. This infection may
be associated with serious outcomes, including deteriorating renal function and
renal graft loss [seeADVERSE REACTIONS]. Patient monitoring may help
detect patients at risk for BK virus-associated nephropathy. Reduction in
immunosuppression should be considered for patients who develop evidence of BK
virus-associated nephropathy.

Cases of progressive multifocal leukoencephalopathy (PML),
sometimes fatal have been reported in patients treated with immunosuppressants,
including Rapamune. PML commonly presents with hemiparesis, apathy, confusion,
cognitive deficiencies and ataxia. Risk factors for PML include treatment with
immunosuppressant therapies and impairment of immune function. In
immunosuppressed patients, physicians should consider PML in the differential
diagnosis in patients reporting neurological symptoms and consultation with a
neurologist should be considered as clinically indicated. Consideration should
be given to reducing the amount of immunosuppression in patients who develop
PML. In transplant patients, physicians should also consider the risk that
reduced immunosuppression represents to the graft.

Interstitial Lung Disease

Cases of interstitial lung disease (including
pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and
pulmonary fibrosis), some fatal, with no identified infectious etiology have
occurred in patients receiving immunosuppressive regimens including Rapamune.
In some cases, the interstitial lung disease has resolved upon discontinuation
or dose reduction of Rapamune. The risk may be increased as the trough
sirolimus concentration increases [see ADVERSE REACTIONS].

De Novo Use Without Cyclosporine

The safety and efficacy of de novo use of Rapamune
without cyclosporine is not established in renal transplant patients. In a
multicenter clinical study, de novo renal transplant patients treated with
Rapamune, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor
antagonist had significantly higher acute rejection rates and numerically
higher death rates compared to patients treated with cyclosporine, MMF,
steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal
function, was not apparent in the treatment arm with de novo use of Rapamune
without cyclosporine. These findings were also observed in a similar treatment
group of another clinical trial.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months
after transplantation, particularly for patients at increased risk for CMV
disease.

Assay For Sirolimus Therapeutic Drug Monitoring

Currently in clinical practice, sirolimus whole blood
concentrations are being measured by various chromatographic and immunoassay
methodologies. Patient sample concentration values from different assays may
not be interchangeable [seeDOSAGE AND ADMINISTRATION].

Skin Cancer Events

Patients on immunosuppressive therapy are at increased
risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be
limited by wearing protective clothing and using a sunscreen with a high
protection factor.

Patient Counseling Information

Advise patients, their families, and their caregivers to
read the Medication Guide and assist them in understanding its contents. The
complete text of the Medication Guide is reprinted at the end of the document.

Dosage

Skin Cancer Events

Patients should be told that exposure to sunlight and
ultraviolet (UV) light should be limited by wearing protective clothing and
using a sunscreen with a high protection factor because of the increased risk
for skin cancer [see WARNINGS AND PRECAUTIONS].

Pregnancy Risks

Women of childbearing potential should be informed of the
potential risks during pregnancy and told that they should use effective
contraception prior to initiation of Rapamune therapy, during Rapamune therapy,
and for 12 weeks after Rapamune therapy has been stopped [see Use in
Specific Populations].

This product's label may have been updated. For current
full prescribing information, please visit www.pfizer.com.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies were conducted in mice and rats.
In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than
the 2 mg daily clinical dose (adjusted for body surface area), there was a
statistically significant increase in malignant lymphoma at all dose levels
compared with controls. In a second mouse study at dosages that were
approximately 3 to 16 times the clinical dose (adjusted for body surface area),
hepatocellular adenoma and carcinoma in males were considered
sirolimus-related. In the 104-week rat study at dosages equal to or lower than
the clinical dose of 2 mg daily (adjusted for body surface area), there were no
significant findings.

Fertility was diminished slightly in both male and female
rats following oral administration of sirolimus at doses approximately 10 times
or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body
surface area). In male rats, atrophy of testes, epididymides, prostate,
seminiferous tubules and/or reduction in sperm counts were observed. In female
rats, reduced size of ovaries and uteri was observed. Reduction of sperm count
in male rats was reversible upon cessation of dosing in one study. Testicular
tubular degeneration was also seen in a 4-week intravenous study of sirolimus
in monkeys at doses that were approximately equal to the clinical dose
(adjusted for body surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Sirolimus was embryo/fetotoxic in rats when given in
doses approximately 0.2 to 0.5 the human doses (adjusted for body surface
area). Embryo/fetotoxicity was manifested as mortality and reduced fetal
weights (with associated delays in skeletal ossification). However, no
teratogenesis was evident. In combination with cyclosporine, rats had increased
embryo/feto mortality compared with sirolimus alone. There were no effects on
rabbit development at a maternally toxic dosage approximately 0.3 to 0.8 times
the human doses (adjusted for body surface area). There are no adequate and
well-controlled studies in pregnant women. Effective contraception must be initiated
before Rapamune therapy, during Rapamune therapy, and for 12 weeks after
Rapamune therapy has been stopped. Rapamune should be used during pregnancy
only if the potential benefit outweighs the potential risk to the embryo/fetus.

Nursing Mothers

Sirolimus is excreted in trace amounts in milk of
lactating rats. It is not known whether sirolimus is excreted in human milk.
The pharmacokinetic and safety profiles of sirolimus in infants are not known.
Because many drugs are excreted in human milk, and because of the potential for
adverse reactions in nursing infants from sirolimus, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Rapamune in pediatric patients
< 13 years have not been established.

The safety and efficacy of Rapamune Oral Solution and
Rapamune Tablets have been established in children ≥ 13 years judged to
be at low-to moderate-immunologic risk. Use of Rapamune Oral Solution and
Rapamune Tablets in this subpopulation of children ≥ 13 years is
supported by evidence from adequate and well-controlled trials of Rapamune Oral
Solution in adults with additional pharmacokinetic data in pediatric renal
transplantation patients [see CLINICAL PHARMACOLOGY].

Safety and efficacy information from a controlled
clinical trial in pediatric and adolescent ( < 18 years of age) renal
transplant patients judged to be at high-immunologic risk, defined as a history
of one or more acute rejection episodes and/or the presence of chronic
allograft nephropathy, do not support the chronic use of Rapamune Oral Solution
or Tablets in combination with calcineurin inhibitors and corticosteroids, due
to the higher incidence of lipid abnormalities and deterioration of renal
function associated with these immunosuppressive regimens compared to
calcineurin inhibitors, without increased benefit with respect to acute
rejection, graft survival, or patient survival [see Clinical Studies].

Geriatric Use

Clinical studies of Rapamune Oral Solution or Tablets did
not include sufficient numbers of patients ≥ 65 years to determine
whether they respond differently from younger patients. Data pertaining to
sirolimus trough concentrations suggest that dose adjustments based upon age in
geriatric renal patients are not necessary. Differences in responses between the
elderly and younger patients have not been identified. In general, dose
selection for an elderly patient should be cautious, usually starting at the
low end of the dosing range, reflecting the greater frequency of decreased
hepatic, or cardiac function, and of concomitant disease or other drug therapy.